Abstract
Ligation of CD40 on monocytes through its interaction with CD40 ligand (CD154) present on activated T helper cells, results in activation of monocyte inflammatory cytokine synthesis and rescue of monocytes from apoptosis induced through serum deprivation. Both of these consequences of CD40 stimulation have been shown to be dependent on the induction of protein tyrosine kinase activity. CD40-mediated activation of protein tyrosine kinase activity and subsequent inflammatory cytokine production are abrogated by treatment of monocytes with the T helper type 2 cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10). In the current study we demonstrate that stimulation of monocytes through CD40 resulted in the phosphorylation and activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinases, whereas phosphorylation of mitogen-activated protein kinases family members p38 and c-Jun N-terminal kinase was not observed in response to this stimuli over the time course examined. PD98059, an inhibitor of the upstream activator of ERK1/2, the MAP/ERK kinase MEK1/2, suppressed IL-1beta and tumor necrosis factor-alpha production in a dose-dependent fashion. Pretreatment of monocytes with IL-4 and IL-10 inhibited CD40-mediated activation of ERK1/2 kinase activity when used individually, and are enhanced in effectiveness when used in combination. Together, the data demonstrate that CD40-mediated induction of IL-1beta and tumor necrosis factor-alpha synthesis is dependent on a MEK/ERK pathway which is obstructed by signals generated through the action of IL-4 and IL-10.
Highlights
From the Departments of ‡Biochemistry and Molecular Biology and **Microbiology, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614 and the ʈImmunopathology Section, NIDR, National Institutes of Health, Bethesda, Maryland 20892
In the current study we demonstrate that stimulation of monocytes through CD40 resulted in the phosphorylation and activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinases, whereas phosphorylation of mitogen-activated protein kinases family members p38 and c-Jun N-terminal kinase was not observed in response to this stimuli over the time course examined
The demonstration that the CD40CD154 interaction contributes to the ability of T cells to activate monocyte/macrophage inflammatory cytokine synthesis suggested that this receptor:ligand pair may contribute to the maintenance and/or exacerbation of autoimmune inflammatory disease
Summary
From the Departments of ‡Biochemistry and Molecular Biology and **Microbiology, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614 and the ʈImmunopathology Section, NIDR, National Institutes of Health, Bethesda, Maryland 20892. Ligation of CD40 on monocytes through its interaction with CD40 ligand (CD154) present on activated T helper cells, results in activation of monocyte inflammatory cytokine synthesis and rescue of monocytes from apoptosis induced through serum deprivation Both of these consequences of CD40 stimulation have been shown to be dependent on the induction of protein tyrosine kinase activity. A broader role of CD40 signaling was revealed through the finding that CD40 is expressed on numerous cell types including, in addition to monocytes, dendritic cells, fibroblasts, keratinocytes, endothelial cells, and vascular smooth muscle cells [5,6,7,8,9,10,11] Stimulation of these cell types through CD40 induces cell functions that contribute to inflammatory responses, such as activation of cytokine synthesis and enhancement of co-stimulatory and adhesion molecule expression [12]. AntiCD154 treatment inhibits the development of experimental autoimmune encephalomyelitis, it was shown that antiCD154 treatment of animals after onset of experimental autoimmune encephalomyelitis reduced the extent and severity of
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